Effect of peer-distributed HIV self-test kits on demand for biomedical HIV prevention in rural KwaZulu-Natal, South Africa: a three-armed cluster-randomised trial comparing social networks versus direct delivery.

Study objective: We investigated two peer distribution models of HIV self-testing (HIVST) in HIV prevention demand creation compared with trained young community members (peer navigators). Methods: We used restricted randomisation to allocate 24 peer navigator pairs (clusters) in KwaZulu-Natal 1:1:1: (1) standard of care (SOC): peer navigators distributed clinic referrals, pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) information to 18–30 year olds. (2) peer navigator direct distribution (PND): Peer navigators distributed HIVST packs (SOC plus two OraQuick HIVST kits) (3) incentivised peer networks (IPN): peer navigators recruited young community members (seeds) to distribute up to five HIVST packs to 18–30 year olds within their social networks. Seeds received 20 Rand (US$1.5) for each recipient who distributed further packs. The primary outcome was PrEP/ART linkage, defined as screening for PrEP/ART eligibility within 90 days of pack distribution per peer navigator month (pnm) of outreach, in women aged 18–24 (a priority for HIV prevention). Investigators and statisticians were blinded to allocation. Analysis was intention to treat. Total and unit costs were collected prospectively. Results: Between March and December 2019, 4163 packs (1098 SOC, 1480 PND, 1585 IPN) were distributed across 24 clusters. During 144 pnm, 272 18–30 year olds linked to PrEP/ART (1.9/pnm). Linkage rates for 18–24-year-old women were lower for IPN (n=26, 0.54/pnm) than PND (n=45, 0.80/pnm; SOC n=49, 0.85/pnm). Rate ratios were 0.68 (95$36) c.f. SOC (US$64). Cost per person linked to PrEP/ART was cheaper in both peer navigator arms compared with IPN. Discussion: HIVST did not increase demand for PrEP/ART. Incentivised social network distribution reached large numbers with HIVST but resulted in fewer linkages compared with PrEP/ART promotion by peer navigators

Optimizing HIV testing services in sub-Saharan Africa: cost and performance of verification testing with HIV self-tests and tests for triage

INTRODUCTION: Strategies employing a single rapid diagnostic test (RDT) such as HIV self-testing (HIVST) or "test for triage" (T4T) are proposed to increase HIV testing programme impact. Current guidelines recommend serial testing with two or three RDTs for HIV diagnosis, followed by retesting with the same algorithm to verify HIV-positive status before anti-retroviral therapy (ART) initiation. We investigated whether clients presenting to HIV testing services (HTS) following a single reactive RDT must undergo the diagnostic algorithm twice to diagnose and verify HIV-positive status, or whether a diagnosis with the setting-specific algorithm is adequate for ART initiation. METHODS: We calculated (1) expected number of false-positive (FP) misclassifications per 10,000 HIV negative persons tested, (2) positive predictive value (PPV) of the overall HIV testing strategy compared to the WHO recommended PPV ≥99%, and (3) expected cost per FP misclassified person identified by additional verification testing in a typical low-/middle-income setting, compared to the expected lifetime ART cost of $3000. Scenarios considered were as follows: 10$5879, $3770, and$24,259 respectively. Results were sensitive to assumptions about accuracy of self-reported reactive results and whether reactive triage test results influenced biased interpretation of subsequent RDT results by the HTS provider. CONCLUSIONS: Diagnosis with the full algorithm following presentation with a reactive triage test is expected to achieve PPV above the 99% threshold. Continuing verification testing prior to ART initiation remains recommended, but HIV testing strategies involving HIVST and T4T may provide opportunities to maintain quality while increasing efficiency as part of broader restructuring of HIV testing service delivery

Cost-per-diagnosis as a metric for monitoring cost effectiveness of HIV testing programmes in low income settings in southern Africa : health economic and modelling analysis

Introduction: As prevalence of undiagnosed HIV declines, it is unclear whether testing programmes will be cost effective. To guide their HIV testing programmes,countries require appropriatemetrics that can be measured. The cost-per-diagnosisis potentially a useful metric. Methods:We simulated a series of setting-scenarios for adult HIV epidemics and ART programmes typical of settings in southern Africa using an individual-based model and projected forward from 2018 under two policies: (i) a minimum package of “core” testing (i.e. testing in pregnant women, for diagnosis of symptoms, in sex workers, and in men coming forward for circumcision) is conducted, and (ii) “core” testing as above plus “additional-testing”, for which we specify different rates of testing and various degrees to which those with HIV are more likely to test than thosewithout HIV. We also considered a plausible range of unit test costs. The aim was to assess the relationship between cost-per-diagnosisand the incremental cost-effectiveness ratio(ICER) of the additional-testingpolicy. Discount rate 3%; costs in 2018 $US. Results:There was a strong graded relationship between the cost-per-diagnosisand the ICER. Overall, the ICERwas below$500 per-DALY-averted (the cost effectiveness threshold used in primary analysis) so long as thecost-per-diagnosiswas below $315. This thresholdcost-per-diagnosiswas similar according to epidemic and programmatic features including the prevalence of undiagnosed HIV, the HIV incidence and a measure of HIV programme quality (the proportion of HIV diagnosed people having a viral load <1000 copies/mL). However, restrictingto women, additional-testingdid not appear cost-effective even at acost-per-diagnosisof below$50, while restrictingto men additional-testingwas cost effective up to a cost-per-diagnosisof $585. Thethreshold cost for testing in men fell to$256 when the cost effectiveness threshold was $300instead of$500, and to $81 when considering a discount rate of 10% perannum.Conclusions:For testing programmesin low income settings in southern African there is an extremely strong relationship between the cost-per-diagnosisand the cost per DALY averted, indicating that the cost-per-diagnosiscan be used to monitor the cost effectiveness of testing programmes

Provider Attitudes toward the Voluntary Medical Male Circumcision Scale-Up in Kenya, South Africa, Tanzania and Zimbabwe.

Countries participating in voluntary medical male circumcision (VMMC) scale-up have adopted most of six elements of surgical efficiency, depending on national policy. However, effective implementation of these elements largely depends on providers' attitudes and subsequent compliance. We explored the concordance between recommended practices and providers' perceptions toward the VMMC efficiency elements, in part to inform review of national policies. As part of Systematic Monitoring of the VMMC Scale-up (SYMMACS), we conducted a survey of VMMC providers in Kenya, South Africa, Tanzania, and Zimbabwe. SYMMACS assessed providers' attitudes and perceptions toward these elements in 2011 and 2012. A restricted analysis using 2012 data to calculate unadjusted odds ratios and 95% confidence intervals for the country effect on each attitudinal outcome was done using logistic regression. As only two countries allow more than one cadre to perform the surgical procedure, odds ratios looking at country effect were adjusted for cadre effect for these two countries. Qualitative data from open-ended responses were used to triangulate with quantitative analyses. This analysis showed concordance between each country's policies and provider attitudes toward the efficiency elements. One exception was task-shifting, which is not authorized in South Africa or Zimbabwe; providers across all countries approved this practice. The decision to adopt efficiency elements is often based on national policies. The concordance between the policies of each country and provider attitudes bodes well for compliance and effective implementation. However, study findings suggest that there may be need to consult providers when developing national policies.\u

Potential conservation of circadian clock proteins in the phylum Nematoda as revealed by bioinformatic searches

Although several circadian rhythms have been described in C. elegans, its molecular clock remains elusive. In this work we employed a novel bioinformatic approach, applying probabilistic methodologies, to search for circadian clock proteins of several of the best studied circadian model organisms of different taxa (Mus musculus, Drosophila melanogaster, Neurospora crassa, Arabidopsis thaliana and Synechoccocus elongatus) in the proteomes of C. elegans and other members of the phylum Nematoda. With this approach we found that the Nematoda contain proteins most related to the core and accessory proteins of the insect and mammalian clocks, which provide new insights into the nematode clock and the evolution of the circadian system.Fil: Romanowski, Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; ArgentinaFil: Garavaglia, Matías Javier. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Goya, María Eugenia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ghiringhelli, Pablo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Golombek, Diego Andres. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Expansion of Cord Blood CD34+ Cells in Presence of zVADfmk and zLLYfmk Improved Their In Vitro Functionality and In Vivo Engraftment in NOD/SCID Mouse

BACKGROUND: Cord blood (CB) is a promising source for hematopoietic stem cell transplantations. The limitation of cell dose associated with this source has prompted the ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs). However, the expansion procedure is known to exhaust the stem cell pool causing cellular defects that promote apoptosis and disrupt homing to the bone marrow. The role of apoptotic machinery in the regulation of stem cell compartment has been speculated in mouse hematopoietic and embryonic systems. We have consistently observed an increase in apoptosis in the cord blood derived CD34(+) cells cultured with cytokines compared to their freshly isolated counterpart. The present study was undertaken to assess whether pharmacological inhibition of apoptosis could improve the outcome of expansion. METHODOLOGY/PRINCIPAL FINDINGS: CB CD34(+) cells were expanded with cytokines in the presence or absence of cell permeable inhibitors of caspases and calpains; zVADfmk and zLLYfmk respectively. A novel role of apoptotic protease inhibitors was observed in increasing the CD34(+) cell content of the graft during ex vivo expansion. This was further reflected in improved in vitro functional aspects of the HSPCs; a higher clonogenicity and long term culture initiating potential. These cells sustained superior long term engraftment and an efficient regeneration of major lympho-myeloid lineages in the bone marrow of NOD/SCID mouse compared to the cells expanded with growth factors alone. CONCLUSION/SIGNIFICANCE: Our data show that, use of either zVADfmk or zLLYfmk in the culture medium improves expansion of CD34(+) cells. The strategy protects stem cell pool and committed progenitors, and improves their in vitro functionality and in vivo engraftment. This observation may complement the existing protocols used in the manipulation of hematopoietic cells for therapeutic purposes. These findings may have an impact in the CB transplant procedures involving a combined infusion of unmanipulated and expanded grafts

Epigenetic Patterns Maintained in Early Caenorhabditis elegans Embryos Can Be Established by Gene Activity in the Parental Germ Cells

Epigenetic information, such as parental imprints, can be transmitted with genetic information from parent to offspring through the germ line. Recent reports show that histone modifications can be transmitted through sperm as a component of this information transfer. How the information that is transferred is established in the parent and maintained in the offspring is poorly understood. We previously described a form of imprinted X inactivation in Caenorhabditis elegans where dimethylation on histone 3 at lysine 4 (H3K4me2), a mark of active chromatin, is excluded from the paternal X chromosome (Xp) during spermatogenesis and persists through early cell divisions in the embryo. Based on the observation that the Xp (unlike the maternal X or any autosome) is largely transcriptionally inactive in the paternal germ line, we hypothesized that transcriptional activity in the parent germ line may influence epigenetic information inherited by and maintained in the embryo. We report that chromatin modifications and histone variant patterns assembled in the germ line can be retained in mature gametes. Furthermore, despite extensive chromatin remodeling events at fertilization, the modification patterns arriving with the gametes are largely retained in the early embryo. Using transgenes, we observe that expression in the parental germline correlates with differential chromatin assembly that is replicated and maintained in the early embryo. Expression in the adult germ cells also correlates with more robust expression in the somatic lineages of the offspring. These results suggest that differential expression in the parental germ lines may provide a potential mechanism for the establishment of parent-of-origin epigenomic content. This content can be maintained and may heritably affect gene expression in the offspring

Preferences for linkage to HIV care services following a reactive self-test: discrete choice experiments in Malawi and Zambia.

OBJECTIVES: The current research identifies key drivers of demand for linkage into care following a reactive HIV self-test result in Malawi and Zambia. Preferences are explored among the general population and key groups such as HIV-positive individuals and adolescents. DESIGN: We used discrete choice experiments (DCEs) embedded in representative household surveys to quantify the relative strength of preferences for various HIV services characteristics. METHODS: The DCE was designed on the basis of a literature review and qualitative studies. Data were collected within a survey (Malawi n = 553, Zambia n = 388), pooled across country and analysed using mixed logit models. Preference heterogeneity was explored by country, age, sex, wealth, HIV status and belief that HIV treatment is effective. RESULTS: DCE results were largely consistent across countries. Major barriers for linkage were fee-based testing and long wait for testing. Community-based confirmatory testing, that is at the participant's or counsellor's home, was preferred to facility-based confirmation. Providing separated waiting areas for HIV services at health facilities and mobile clinics was positively viewed in Malawi but not in Zambia. Active support for linkage was less important to respondents than other attributes. Preference heterogeneity was identified: overall, adolescents were more willing to seek care than adults, whereas HIV-positive participants were more likely to link at health facilities with separate HIV services. CONCLUSION: Populations in Malawi and in Zambia were responsive to low-cost, HIV care services with short waiting time provided either at the community or privately at health facilities. Hard-to-reach groups could be encouraged to link to care with targeted support